Matlock, William; Rodger, Gillian; Pritchard, Emma; Colpus, Matthew; Kapel, Natalia; Barrett, Lucinda; Morgan, Marcus; ... Stoesser, Nicole; + view all Matlock, William; Rodger, Gillian; Pritchard, Emma; Colpus, Matthew; Kapel, Natalia; Barrett, Lucinda; Morgan, Marcus; Oakley, Sarah; Hopkins, Katie; Roohi, Aysha; Karageorgopoulos, Drosos; Avison, Matthew; Walker, Sarah; Lipworth, Samuel; Stoesser, Nicole; - view fewer (2025) Escherichia coli phylogeny drives co-amoxiclav resistance through variable expression of TEM-1 beta-lactamase. Nature Communications (In press).

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Abstract

Co-amoxiclav (amoxicillin and clavulanate) is a commonly used combination antibiotic, with resistance in Escherichia coli associated with increased mortality. The class A beta-lactamase blaTEM-1 is often carried by resistant E. coli but exhibits high phenotypic heterogeneity, complicating genotype-phenotype predictions. We curated a dataset of n=377 diverse E. coli isolates where the only acquired beta-lactamase was blaTEM-1. We generated hybrid assemblies and co-amoxiclav minimum inhibitory concentrations (MICs), and blaTEM-1 qPCR expression data for a subset (n=67/377). We first tested whether intrinsic expression of blaTEM-1 varied between E. coli lineages, for example, from regulatory system differences, which are challenging to genomically quantify. Using genotypic features, we built a hierarchical Bayesian model for blaTEM-1 expression, controlling for phylogeny. Expression varied across the phylogeny, with some lineages (phylogroups B1 and C, ST12) expressing blaTEM-1 more than others (phylogroups E and F, ST372). Next, we built a second model to predict isolate MIC from genotypic features, again controlling for phylogeny. Phylogeny alone shifted MIC past the clinical breakpoint in 19% (55/292) of isolates with greater-than-chance probability, mostly representing ST12, ST69, and ST127. A third causal model confirmed that phylogenetic influence on blaTEM-1 expression drove variation in MIC. We speculate that intergenic variation underlies this effect.

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